We are not winning the war against HIV. For each person treated with potent antiretroviral therapy, 6 new individuals became infected. Without a foreseeable cure, prevention is the medicine needed to control the HIV epidemic. A particularly critical need is one of coitally-independent dosing strategies which women can initiate and are imperceptible to their partners. Topical formulations such as gels and vaginal rings are being investigated, but oral antiretroviral drugs also hold significant promise for prevention. With the support of this planning grant, we will develop a novel, scientifically-based method of preventing HIV infection with oral antiretroviral drugs by targeting genital tract and rectal mucosal tissue drug concentrations. This integrated approach will address the challenge of preventing HIV infection by finding the appropriate concentration of antiretroviral to deliver to the appropriate biological site for the proper length of time. Our objectives are to develop pharmacokinetic models of selected antiretrovirals in cervical, vaginal, and rectal secretions and tissues;use explant human tissue cultures to identify the tissue concentrations of the select antiretrovirals which prevent HIV infection;to model the resulting pharmacokinetic and pharmacodynamic data to select a coitally-independent preventative drug regimen most likely to be effective in women at all tissue sites;and to determine the efficacy of this selected regimen in a proof-of-concept trial. The specific aims of the planning grant are to develop the clinical trial protocols, informed consents, and other documents necessary for regulatory review;to obtain approval from the series of requisite review committees and establish the data safety monitoring committee, and to develop the necessary clinical trial infrastructure and acquire the study agents. This planning grant will provide the infrastructure to develop three clinical protocols for prevention of HIV infection. Successful completion of these protocols will result in a new strategy for identifying oral compounds for HIV prevention, as they will define, for the first time, the extracellular and intracellular human tissue concentrations of antiretrovirals required to prevent HIV infection. When combined with the knowledge of achievable concentrations in mucosal tissues using standard doses of antiretrovirals, the antiretrovirals which have the most likely probability of success in Phase II/III studies of coitally-independent pre-exposure prophylaxis regimens can be selected. This will help maximize the return on investment of expensive randomized controlled trials.